title: A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.
abstract: Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.
authors.affiliation: Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA, shurvitz@mednet.ucla.edu.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Ruth M
authors.initials: RM
authors.lastname: O'Regan
authors.forename: Vivianne C
authors.initials: VC
authors.lastname: Tjan-Heijnen
authors.forename: Joseph
authors.initials: J
authors.lastname: Gligorov
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart
authors.forename: Haresh
authors.initials: H
authors.lastname: Jhangiani
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Mirshahidi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tan-Chiu
authors.forename: Sara
authors.initials: S
authors.lastname: Miao
authors.forename: Mona
authors.initials: M
authors.lastname: El-Hashimy
authors.forename: Jeremie
authors.initials: J
authors.lastname: Lincy
authors.forename: Tetiana
authors.initials: T
authors.lastname: Taran
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Tarek
authors.initials: T
authors.lastname: Sahmoud
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D017211:Treatment Failure
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068338:Everolimus; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human